TABLE 1.

Anti-dengue virus activities and in vitro stability profiles of cyclic phosphoramidate prodrugs of 6-O-alkyl-2′-deoxy-2′-fluoro-2′-C-methylguanosine^a

Compound	R1b	R2c	R3	Sp or Rp	PBMC EC50 (μM)d	t1/2 (min) in plasma in:			t1/2 (min) in liver S9 fraction in:		t1/2 (min) in intestinal S9 fraction in:
						Human	Dog	Rat	Human	Dog	Human	Dog
4e				Rp	>25	>120	NDf	>120	>120	ND	ND	ND
5e				Sp	0.17	>120	>120	<5	18	51	>120	72
12	i-Pr	Me (l-Ala)	Et	Sp	0.072	>120	>120	<5	36	56	>120	>120
13	i-Pr	Me (l-Ala)	Et	Rp	0.67	>120	>120	<5	63	110	>120	>120
14	i-Pr	Me (d-Ala)	Et	Sp	0.37	>120	>120	6	>120	>120	>120	>120
15	i-Pr	Me (d-Ala)	Et	Rp	1.1	>120	>120	6	105	73	ND	ND
16	i-Pr	H (Gly)	Et	Rp	0.33	>120	>120	<5	58	91	ND	ND
17	Et	Me (l-Ala)	Et	Rp	0.23	>120	>120	<5	76	116	>120	>120
18	Me	Me (l-Ala)	Et	Rp	0.46	>120	>120	<5	>120	>120	>120	>120
19	Me	Me (l-Ala)	i-Pr	Rp	0.43	113	>120	<5	>120	>120	ND	ND
20	Et	i-Pr (d-Val)	Et	Sp	0.23	>120	>120	66	82	61	>120	>120

^aThe structure of 6-O-alkyl-2′-deoxy-2′-fluoro-2′-C-methylguanosine with associated R groups is shown in Fig. 1C.

^bi-Pr, iso-propyl; Et, ethyl; Me, methyl.

^cThe associated amino acid is shown in parentheses.

^dDENV-2 plaque assay in human PBMCs.

^eStructure is shown in Fig. 1B.

^fND, not done.